Polysaccharide lyases degrade anionic polysaccharides that are important in bacterial biofilm formation and host-pathogen interactions.
Stenotrophomonas maltophilia is a ubiquitous, gram-negative bacteria that has become an increasingly important nocosomial pathogen in immunocompromised patients. Approximately 1% of all nosocomal bacteraemias are due to S. maltophilia infection, with the attributed mortality rate at nearly 28%, which places it among the highest attributed mortality rates observed for nosocomal bacteraemias. A major reason for the high mortality associated with S. maltophilia is its nearly universal resistance to broad-spectrum antibiotics such as imipenem and aminoglycosides, and increasing resistance to last-line′ cephelasporin antibiotics such as ceftazidime and cefotaxime.
One unique mechanism that S. maltophilia has evolved to become multi-drug resistant (MDR) is its production of highly branched, anionic exopolysaccharides (EPS) to form biofilms. Biofilms are comprised of secreted, high molecular weight EPS such as alginic acid, which encapsulate a population of bacterial cells to create a ‘niche’ environment that is often impermeable to antimicrobials, detergents or other organic compounds.
While several pathogenic bacteria are capable of producing alginic acid biofilms, S. maltophilia is unique in that the EPS that comprise the biofilm are highly anionic due to the addition of branched poly-D-galacturonic acid (HexA)-ethyl-D-lactate (Lac) chains. Recent studies indicate the additional negative charge of S. maltophilia EPS due to the branched HexA-Lac group enables biofilm binding to metallic or plastic surfaces, as well as creating a heat-, acid- and detergent-resistant environment that allows S. maltophilia to colonize water purification systems, ventilators and stents. As a result, S. maltophilia is the 2nd leading cause of ventilator-associated pneumonia, with over 70% of all S. maltophilia-specific, ventilator-associated MDR infections caused by biofilm forming strains.
In biofilm-positive MDR infections, surgery is the main option to either remove infected lung tissue or perform a lung transplant, although both are often not feasible since the patient is immunocompromised and therefore at greater risk of additional infections. This is especially a problem for cystic fibrosis (CF) patients, in which accumulation of mucin in the lungs creates a viscous, damp environment in which biofilm-producing S. maltophilia can thrive. S. maltophilia is the 2nd most common cause of chronic infection in CF patients after P. aeruginosa, with estimates as high as 20% of all MDR infections. Thus, biofilm formation plays a central role in the pathogenicity of S. maltophilia, and strategies targeting EPS degradation will enable more effective treatments to prevent chronic S. maltophilia infection, particularly in CF and immunocompromised patients.
Embodiments of the present invention are directed to these and other ends.